Amide derivatives as NMDA receptor antagonists

ABSTRACT

Compounds having NR2B selective NMDA receptor antagonist activity are disclosed of the formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             wherein
           one of the neighboring R 1 , R 2 , R 3  and R 4  groups is hydroxy, and the others are each hydrogen atoms,   R 5  and R 6  together with the nitrogen between them form a saturated or unsaturated, 4-6 membered heterocyclic ring, which is substituted by phenoxy, phenyl-(C 1 -C 4  alkyl), phenyl-(C 1 -C 4  alkoxy), phenoxy-(C 1 -C 4  alkyl), or benzoyl, optionally substituted on the aromatic ring by one or more halogen atoms, cyano or hydroxy groups, C 1 -C 4  alkyl or C 1 -C 4  alkoxy   
         
             groups, 
             X is NH—, 
             Y is a nitrogen atom, 
             or pharmaceutically acceptable salts thereof formed with acids or bases.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of Ser. No. 10/412,977 filed 11 Apr.2003 now U.S. Pat. No. 6,919,355 which is a continuation-in-part ofInternational Application PCT/HU01/00099, with an international filingdate of 15 Oct. 2001, published in English under PCT Article 21(2) andnow abandoned, and which claims the priority of Hungarian PatentApplication P00 04123 filed 24 Oct. 2000.

FIELD OF THE INVENTION

The invention relates to new NMDA receptor antagonist carboxylic acidamide derivatives of formula (I)

-   -   wherein

one of the neighboring R¹, R², R³ and R⁴ groups is OH or NH2 and theothers are each hydrogen, or

-   -   two of the neighboring R¹, R², R³ and R⁴ groups in given case        together with one or more identical or different additional        hetero atom and —CH═ and/or —CH₂— groups form a 5-6 membered        homo- or heterocyclic ring, preferably pyrrole, pyrazole,        imidazole, oxazole, oxo-oxazolidine, or 3-oxo-1,4-oxazine ring,        and the other two of R¹, R², R³ and R⁴ groups are hydrogen        atoms,    -   R⁵ and R⁶ together with the nitrogen between them form a        saturated or unsaturated, 4-6 membered heterocyclic ring, which        is substituted by hydroxy group, and/or in given case phenyl or        phenoxy, phenyl-(C₁-C₄ alkyl), phenyl-(C₁-C₄ alkoxy),        phenoxy-(C₁-C₄ alkyl), anilino, phenyl-(C₁-C₄ alkylamino),        [phenyl-(C₁-C₄ alkyl)]-amino, benzoyl, hydroxy-diphenylmethyl,        C₁-C₄ alkoxycarbonyl-phenoxymethyl or benzhydrylidene group,        optionally substituted on the aromatic ring by one or more        halogen atom, cyano or hydroxy group, C₁-C₄ alkyl or C₁-C₄        alkoxy group,    -   X is independently oxygen, —NH— or a CH2 group,    -   Y is independently a nitrogen atom or a —CH— group, and the        salts thereof formed with acids and bases.

As the invention relates also to the salts of compounds of formula (I)formed with acids or bases, especially the salts formed withpharmaceutically acceptable acids or bases, the meaning of compound offormula (I) is either the free compound or the salt even if it is notreferred separately.

An especially significant group of the invention is the compounds offormula (Ia),

-   -   wherein the meaning of R¹, R², R³, R⁴, R⁵ and R⁶ is as described        for the compounds of formula (I).

Especially important carboxylic acid amide derivatives of formula (I)are the following:

6-(4-benzylpiperidine-1-carbonyl)]-1,5-dihydro-oxazolo[4,5-f]indole-2-one,

6-[4-(4-fluorobenzylpiperidine-1-carbonyl)]-1,5-dihydro-oxazolo[4,5-f]indole-2-one,

(4-benzylpiperidine-1-yl)-(3,6-dihydro-pyrrolo[3,2-e]indazol-7-yl)methanone,

[4-(4-fluorobenzylpiperidine-1-yl)]-(3,6-dihydro-pyrrolo[3,2-e]indazol-7-yl)methanone,

(4-p-tolyloxypiperidine-1-yl)]-(3,6-dihydro-pyrrolo[3,2-e]indazol-7-yl)methanone,

(4-benzylpiperidine-1-yl)-(3,6-dihydro-imidazo[4,5-e]indol-7-yl)methanone.

The invention also relates to the pharmaceutical compositions containingthe compounds of formula (I) as active ingredient.

Furthermore objects of the present invention are the synthesis ofcompounds of formula (I), and the chemical and pharmaceuticalmanufacture of medicaments containing these compounds, as well as themethod of treatments with these compounds, which means administering toa mammal to be treated—including human—effective amount/amounts ofcompounds of formula (I) of the present invention as such or asmedicament.

The term “halogen” substituent—as defined earlier—denotes fluorine,chlorine, bromine or iodine atoms, preferably fluorine and chlorineatoms. The term C₁-C₄ alkyl group used in the present descriptiondenotes methyl, ethyl, normal- and isopropyl and different butyl groups.These C₁-C₄ alkyl groups can be in the C₁-C₄ alkoxy groups. The termC₁-C₆ alkanoyloxy group denotes a monovalent acyloxy group consisting ofa hydrogen atom, as well as a C₁-C₆ alkyl group and a carbonyl-oxy group(—CO—O—) attached to it, preferably a formyloxy, an acetoxy, apropionyloxy, different butiryloxy, valeroyloxy and caproyloxy groups.

The invention relates also to the salts of compounds of formula (I)formed with acids or bases.

Both organic and inorganic acids can be used for the formation of acidaddition salts. Suitable inorganic acids can be for example hydrochloricacid, sulfuric acid and phosphoric acid. Representatives of monovalentorganic acids can be for example formic acid, acetic acid, propionicacid, and different butyric acids, valeric acids and capric acids.Representatives of bivalent organic acids can be for example oxalicacid, malonic acid, maleic acid, fumaric acid and succinic acid. Otherorganic acids can also be used, such as hydroxy acids for example citricacid, tartaric acid, or aromatic carboxylic acids for example benzoicacid or salicylic acid, as well as aliphatic and aromatic sulfonic acidsfor example methanesulfonic acid and p-toluenesulfonic acid. Especiallyvaluable group of the acid addition salts is in which the acid componentitself does not have therapeutical effect in the applied dose or it doesnot have unfavorable influence on the effect of the active ingredient.These acid addition salts are pharmaceutically acceptable acid additionsalts. The reason why acid addition salts, which do not belong to thepharmaceutically acceptable acid addition salts belong to the presentinvention is, that in given case they can be advantageous in thepurification and isolation of the desired compounds.

Among the salts formed with bases especially important are the saltsformed with alkali metals, for example sodium, potassium, alkaline-earthmetals, for example calcium and magnesium, as well as with ammonia ororganic amines. The latter bases can have further substituents, forexample hydroxy or amino groups, which can influence e.g. the solubilityand the handling of the product.

According to the invention the compounds of formula (I) are synthesizedby forming an amide bond between a carboxylic acid of formula (II)

-   -   wherein the meaning of R¹, R², R³, R⁴, X and Y are as described        before for the formula of (I)—and an amine of formula (III)

wherein the meaning of R⁵ and R⁶ are as given before for the formula of(I),then the so obtained carboxylic acid amide derivative of formula(I)—wherein the meaning of R¹, R², R³, R⁴, R⁵, R⁶, X and Y is as definedfor the formula of (I)—in given case is transformed into an othercompound of formula (I) by introducing new substituents and/or modifyingor removing the existing ones, and/or salt formation and/or liberatingthe compound from salts, and/or the obtained racemates are resolvedusing optical active acids or bases by known methods.

The amide bond formation is preferably carried out by preparing anactive derivative from a carboxylic acid of formula (II) and this isreacted with an amine of formula (III) preferably in the presence of abase.

In solution the transformation of a carboxylic acid into an activederivative is carried out in situ during the amide bond formation in aproper solvent (for example dimethylformamide, acetonitrile, chlorinatedhydrocarbons or hydrocarbons). The active derivatives can be acidchlorides (for example prepared from carboxylic acid with thionylchloride), mixed anhydrides (for example prepared from carboxylic acidwith isobutyl chloroformate in the presence of a base, e.g.triethylamine), active esters (for example prepared from carboxylic acidwith hydroxybenztriazol and dicyclohexyl-carbodiimide orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) in the presence of a base e.g. triethylamine). The activederivatives are prepared between room temperature and 0° C. To the soobtained solution or suspension a proper amine of formula (III) is addedas base or as a salt formed with inorganic acid so that base, forexample triethylamine, needed for the liberation of the amine is addedto the reaction mixture separately. The condensation reactions arefollowed by thin layer chromatography. The necessary reaction time is6-20 h. The work-up of the reaction mixture can be carried out bydifferent methods.

When the reaction mixture is a suspension, the precipitate is filteredoff and recrystallized from a proper solvent to give the pure product.If the crystallization does not lead to the pure product, then columnchromatography can be used for the purification of it. The columnchromatography is carried out either on normal phase using Kieselgel 60as adsorbent and different solvent systems, e.g. toluene/methanol,chloroform/methanol or toluene/acetone, as eluents, or on reverse phaseusing Prep-Pak-500/C18 type packings (produced by Waters Associates) andacetonitrile/water/trifluoroacetic acid as eluent. If the reactionmixture is a solution at the end of the acylation, it is concentrated,and the residue is crystallized or purified by column chromatography asdescribed above. The structures of the products are determined by IR,NMR and mass spectrometry.

Alternatively, the reaction mixture can be purified by columnchromatography without concentration at the end of the reaction. Thefractions having the desired compound are concentrated, the residue isdissolved in dimethylsulfoxide and the structure, the purity as well asthe concentration of the product is determined by HPLC/MS (high pressurecolumn chromatography, followed by mass spectrometry).

The obtained carboxylic acid amide derivatives of formula(I)—independently from the method of preparation—in given case can betransformed into an other compound of formula (I) by introducing furthersubstituents and/or modifying and/or removing the existing ones, and/orformation of salts with acids and/or liberating the carboxylic acidamide derivative of formula (I) from the obtained acid addition salts bytreatment with a base and/or the free carboxylic acid amide derivativeof formula (I) can be transformed into a salt by treatment with a base.

The carboxylic acids of formula (II) and the amines of formula (III) areeither commercially available or can be synthesized by different knownmethods. The syntheses of some commercially not available carboxylicacid of formula (II) are described in the Examples. Following theseprocedures the other commercially not available carboxylic acids offormula (II) can also be prepared.

The compounds of the invention as well as their pharmaceuticallyacceptable salts can be used as such or suitably in the form ofpharmaceutical compositions. These compositions (drugs) can be in solid,liquid or semiliquid form and pharmaceutical adjuvant and auxiliarymaterials can be added, which are commonly used in practice, such ascarriers, excipients, diluents, stabilizers, wetting or emulsifyingagents, pH- and osmotic pressure-influencing, flavoring or aromatizing,as well as formulation-promoting or formulation-providing additives.

The dosage required to exert the therapeutical effect can vary withinwide limits and will be fitted to the individual requirements in each ofthe particular case, depending on the stage of the disease, thecondition and the bodyweight of the patient to be treated, as well asthe sensitivity of the patient against the active ingredient, route ofadministration and number of daily treatments. The actual dose of theactive ingredient to be used can safely be determined by the attendingphysician skilled in the art in the knowledge of the patient to betreated.

The pharmaceutical compositions containing the active ingredientaccording to the present invention usually contain 0.01 to 100 mg ofactive ingredient in a single dosage unit. It is, of course possiblethat the amount of the active ingredient in some compositions exceedsthe upper or lower limits defined above.

The solid forms of the pharmaceutical compositions can be for exampletablets, dragées, capsules, pills or lyophilized powder ampoules usefulfor the preparation of injections. Liquid compositions are theinjectable and infusable compositions, fluid medicines, packing fluidsand drops. Semiliquid compositions can be ointments, balsams, creams,shaking mixtures and suppositories.

For the sake of a simple administration it is suitable if thepharmaceutical compositions comprise dosage units containing the amountof the active ingredient to be administered once, or a few multiples ora half, third or fourth part thereof. Such dosage units are e.g.tablets, which can be powdered with grooves promoting the halving orquartering of the tablet in order to exactly administer the requiredamount of the active ingredient.

Tablets can be coated with an acid-soluble layer in order to assure therelease of the active ingredient content after leaving the stomach. Suchtablets are enteric-coated. A similar effect can be achieved also byencapsulating the active ingredient.

The pharmaceutical compositions for oral administration can contain e.g.lactose or starch as excipients, sodium carboxymethylcellulose,methylcellulose, polyvinyl pyrrolidine or starch paste as binders orgranulating agents. Potato starch or microcrystalline cellulose is addedas disintegration agents, but ultraamylopectin or formaldehyde caseincan also be used. Talcum, colloidic silicic acid, stearin, calcium ormagnesium stearate can be used as antiadhesive and lubricants.

The tablet can be manufactured for example by wet granulation, followedby pressing. The mixed active ingredients and excipients, as well as ingiven case part of the disintegrants are granulated with an aqueous,alcoholic or aqueous alcoholic solution of the binders in an appropriateequipment, then the granulate is dried. The other disintegrants,lubricants and antiadhesive agents are added to the dried granulate, andthe mixture is pressed to a tablet. In given case the tablets are madewith halving groove to ease the administration.

The tablets can be made directly from the mixture of the activeingredient and the proper auxiliaries by pressing. In given case, thetablets can be coated by using additives commonly used in thepharmaceutical practice, for example stabilizers, flavoring, coloringagents, such as sugar, cellulose derivatives (methyl- or ethylcellulose,sodium carboxymethylcellulose, etc), polyvinyl pyrrolidone, calciumphosphate, calcium carbonate, food coloring agents, food laces, aromaagents, iron oxide pigments, etc. In the case of capsules the mixture ofthe active ingredient and the auxiliaries is filled into capsules.

Liquid oral compositions, for example suspensions, syrups, elixirs canbe made by using water, glycols, oils, alcohols, coloring and flavoringagents.

For rectal administration the composition is formulated in suppositoriesor clysters. The suppository can contain beside the active ingredient acarrier, so called adeps pro suppository. Carriers can be vegetableoils, such as hydrogenated vegetable oils, triglycerides of C₁₂-C₁₈fatty acids (preferably the carriers under the trade name Witepsol). Theactive ingredient is homogeneously mixed with the melted adeps prosuppository and the suppositories are moulded.

For parenteral administration the composition is formulated as injectionsolution. For manufacturing the injection solution the activeingredients are dissolved in distilled water and/or in different organicsolvents, such as glycolethers, in given case in the presence ofsolubilizers, for example polyoxyethylensorbitane-monolaurate,-monooleate, or monostearate (Tween 20, Tween 60, Tween 80). Theinjection solution can also contain different auxiliaries, such asconserving agents, for example ethylendiamine tetraacetate, as well aspH adjusting agents and buffers and in given case local anaesthetic,e.g. lidocain. The injection solution containing the active ingredientof the invention is filtered before it is filled into ampoules, and itis sterilized after filling.

If the active ingredient is hygroscopic, then it can be stabilized byliophylization.

Close structure analogs of the carboxylic acid amide derivatives offormula (I) are known from the literature.

Substituted indole-2-yl-carbonyl-piperidine derivatives, similar to thecompounds of the invention, are described in patent No. WO 9618628 andtwo publications [J. Med. Chem., 39, 3769. (1996), and J. Med. Chem.,42, 4140. (1999)]. These compounds having reverse transcriptaseinhibiting effect can be used for treatment of AIDS patients.

Indole-2-carboxylic acid amides are also known [Bioorg. Med. Chem.Letters, 10, 483. (2000)] to inhibit pp60^(c-arc) tyrosine kinase, andtherefor they can play a role in treatment of tumor patients. Thepublication does not describe NMDA receptor antagonist effect.

Benzofuran-2-yl-piperidine derivatives are described in patent No. WO2000012074. These compounds have p38-a kinase inhibiting effect, andtherefor can be used for treatment of infections caused by gram-negativebacteria as well as of patients suffering from respiratory distresssyndrome.

A methanone derivative described in Protein Sci., 6(7), 1412. (1997)have thrombin inhibiting effect. The publication does not describe NMDAreceptor antagonist effect.

Surprisingly it was found, that in contrast to the known, structurallyanalog compounds—which are known to have only different enzymeinhibiting effects—the new carboxylic acid amide derivatives of formula(I) of the present invention are highly effective and selectiveantagonists of NMDA (N-methyl-D-aspartate) receptors, and moreover mostof the compounds are selective antagonist of NR2B subtype of NMDAreceptor. This selectivity is particularly important, as the undesiredside effects of the compounds are less pronounced.

Antagonists of the NMDA receptors can be used in many disorders that areaccompanied with excess release of glutamate, the main excitatoryneurotransmitter in the central nervous system. Overactivation of NMDAreceptors by glutamate can lead to calcium overload of the cells. Thiscan trigger cascade of intracellular events that can alter the cellfunction and can lead even to death of neurons [TINS, 10, 299-302(1987)].

Our knowledge of NDA receptor structure, function and pharmacology hasexpanded owing to recent achievements of molecular biology. The NMDAreceptors are heteromeric assemblies built up from at least one NR1subunit and at least one of the four NR2 subunits (NR2A-D). Both spatialdistributions in CNS and pharmacological sensitivity of NMDA receptorsbuilt up from various NR2 subunits are different. Particularlyinteresting of these is NR2B subunit, because of its restricteddistribution (highest density is in forebrain and substantia gelatinosaof spinal cord). Compounds selective for this subtype are available[Curr. Pharm. Des. 5, 381-404 (1999)] and were proven to be effective inanimal models of stroke [Stroke 28, 2244-2251 (1997)], traumatic braininjury [Brain Rest 792, 291-298 (1998)], Parkinson's disease [Exp.Neurol. 163, 239-243 (2000)], neuropathic and inflammatory pain[Neuropharmacology 38, 611-623 (1999)]. Subtype selective antagonists ofNDA receptors are expected to exhibit little or no untoward side effectscaused by non-selective antagonists of NMDA receptors acting atglutamate binding site or within the channel pore.

Disorders known to be responsible to NMDA antagonists [Drug NewsPerspect 11, 523-569 (1998), WO 00/00197 international patentapplication] are cerebral ischemia of any origin (e.g. stroke, heartsurgery), chronic neurodegenerative disorders, such as Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis (ALS),Huntington's disease, human immunodeficiency virus (HIV) relatedneuronal injury, traumatic injury of brain or spinal cord, pain (e.g.posttraumatic or postoperative) and chronic pain states, such asneuropathic pain or cancer related pain. NMDA receptor antagonists mayalso be used in epilepsy, anxiety, depression, migraine, psychosis,muscular spasm, multiinfarct dementia and in dementia of other origin,hypoglycemia, degenerative disorders of the retina (e.g. CMV retinitis)asthma, tinnitus, aminoglycoside antibiotic-induced hearing loss. AnNMDA antagonist can be useful to decrease tolerance and/or dependence toopioid treatment of pain, and for treatment of withdrawal syndrome ofe.g. alcohol, opioids, and cocaine.

As the target compounds have the above mentioned biological effects,objects of the present invention are also the process of treatments withcarboxylic acid amide derivatives of formula (I), or with the saltsthereof, which means administering to a mammal to be treated—includinghuman—effective amount/amounts of compounds of formula (I) of thepresent invention as such or as medicament.

It is known that during postnatal development the subunit composition ofneuronal NMDA receptors is changing. Similar change was detected inneuronal cell cultures [Eur. J. Neurosci. 10, 1704-1715 (1998)].According to literature data and to our own immunocitochemicalexaminations neuronal cells cultured for 4-7 days in vitro predominantlyexpress the NR2B subunit, together with NR1 subunit. So functional testof NMDA antagonism in these cells mostly reflects action on NR2B subunitcontaining receptors. Since NMDA receptors are known to be permeable tocalcium ions upon excitation, we characterized the NMDA receptoractivation by measurement of rise in intracellular calcium concentrationfollowing the agonist (NMDA) application to the cells.

Assessment of NMDA Antagonist Potency In Vitro by Measurement ofIntracellular Calcium Concentration with a Plate Reader Fluorimeter

The intracellular calcium measurements were carried out on primaryneocortical cell cultures derived from 17 day old Charles River ratembryos (for the details on the preparation of neocortical cell culturesee Johnson, M. I.; Bunge, R. P. (1992): Primary cell cultures ofperipheral and central neurons and glia. In: Protocols for Neural CellCulture, eds: Fedoroff, S.; Richardson A., The Humana Press Inc.,13-38.) After isolation the cells were plated onto standard 96-wellmicroplates and the cultures were maintained in an atmosphere of 95%air-5% CO₂ at 37° C. until the calcium measurements.

The cultures were used for the intracellular calcium measurements after4-7 days in vitro. Before the measurement the cells were loaded with afluorescent Ca²⁺-sensitive dye, Fluo-4/AM (2-2.5 μM). To stop theloading the cells were washed twice with the solution used for themeasurement (140 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 5 mM HEPES, 5 mMHEPES-Na, 20 mM glucose, 10 μM glycine, pH=7.4). After washing the testcompounds were added to the cells in the above solution (90 μl/well).Intracellular calcium measurements were carried out with a plate readerfluorimeter:elevation of Fluo-4-fluorescence and so, intracellularcalcium was induced by application of 40 μm NMDA. Inhibitory potency ofthe test compounds was assessed by measuring the reduction in thecalcium elevation in the presence of different concentrations of thecompounds. After the measurement a standard calibration procedure withslight modifications was used to convert the fluorescent data to calciumconcentration values [Meth. Cell. Biol. 40, 155-181 (1994)].

Dose-response curves and IC₅₀-values were calculated by using dataderived from at least three independent experiments. Inhibitory potencyof a compound at a single concentration point was expressed as percentinhibition of the NMDA response. Sigmoidal concentration-inhibitioncurves were fit to the data and IC₅₀ values were determined as theconcentration that produces half of the maximal inhibition caused by thecompound.

In Table 1 IC₅₀ values for the most effective compounds of thisinvention measured in this test are listed (column 1-2) together withmost effective reference compounds examined (column 3-4).

TABLE 1 NMDA Code of NMDA Code number of IC₅₀ reference IC₅₀ compound[μM] compound [μM] 4570001461 0.017 Co-101244 0.023 4570001689 0.020 EMD95885 0.035 4570001690 0.022 CP 101,606 0.041 4570001484 0.041 Co-1111030.060 4570002260 0.042 Ro 25.6981 0.159 4570001779 0.050 ifenprodil0.483 4570001662 0.058 4570001462 0.079 4570001688 0.088 45700023400.127 4570001661 0.150 4570001972 0.193 4570001971 0.328   4514305 0.3924570002045 0.44   4513579 0.018   4513848 0.09 4570001103 0.00224570001378 0.009

The reference compounds are as follows:

-   Co 101244:    1-[2-(4-hydroxyphenoxy)ethyl]-4-hydroxy-4-(4-methylbenzyl)piperidine-   EMD 95885:    6-[3-(4-fluorobenzyl)piperidine-1-yl]propionyl]-2,3-dihydro-benzoxazol-2-on-   CP-101,606: (1S,    2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidine-1-yl)-1-propanol-   Co-111103: 1-[2-(4-hydroxyphenoxy)    ethyl]-4-(4-fluorobenzyl)piperidine-   Ro 256981: R-(R*,    S*)-1-(4-hydroxyphenyl)-2-methyl-3-[4-(phenylmethyl)piperidin-1-yl]-1-propanol.

As Table 1 shows, many of the compounds of this invention exceeds thepotency of the known reference compounds examined by us.

Testing Subunit Selectivity on Cells Expressing Recombinant Rat NMDAReceptors

In order to prove NR2B subunit selectivity of the compounds, cellstransfected with cDNAs of the rat NR1a and NR2A or NR2B subunits wereused. Genes cloned according to published sequences [gi508809 (ratNR1a), gi205738 (rat NR2B), gi2905805 (rat NR2A)] were inserted intoinducible mammalian expression vectors bearing different resistancegenes (hygromycine in case of NR1a or neomycine in case of NR2subunits). The vector constructs were introduced into HEK293 cells usinga cationic lipid-mediated transfection method. Protein expression wasinduced by 3 μM MuristeronA. Cells were maintained in the presence of365 μM ketamine for 48-72 hours under an atmosphere of 95% air-5% CO₂ at37° C. before the experiments.

Assessment of NMDA Antagonist Potency on Cells Transfected withNR1a/NR2B Subunits—Fluorimetric Method

For establishment of cell clones stably expressing NR1a/NR2B receptors,transfected cells were exposed to the selecting antibiotics for 4 weeksthen resistant clones were grown up. The expression of NR2B subunitprotein was verified by a flow cytometry based immunocytochemicalmethod. Positive clones were further tested for functional activity inpatch clamp experiments. The best clone producing the highest NMDAevoked ion-current was used for testing NMDA antagonism by measuringNMDA induced elevation of cytosolic calcium concentration. Induction ofprotein expression and maintenance of cells were the same as describedabove.

The cells were plated onto standard 96-well microplates. A platereader-based fluorometric assay was used to measure NMDA antagonism. Themethod was essentially similar to that described above for testingprimary cultures of rat cortical neurons.

Assessment of NMDA Antagonist Potency on Cells Transfected withNR1a/NR2A Subunits—Patch Clamp Method

Cells transiently expressing NR1a/NR2A receptors and grown ontocoverslips were used in patch clamp experiments. Whole-cell patch clamprecording was done according to the standard technique. Cell cultureswere constantly superfused with an extracellular solution (140 mM NaCl,5 mM KCl, 5 mM Hepes, 5 mM Na-Hepes, 2 mM CaCl₂, 20 mM glucose, 10 μMglycine, pH 7.35) at room temperature. Patch pipettes with resistancebetween 3 and 6 M Ω were filled with an intracellular solution (140 mMCsCl, 11 mM EGTA, and 10 mM Hepes, pH 7.3). The inward current elicitedby 100 μM NMDA was recorded from cells voltage clamped at −70 mV.Compounds were applied via a multibarrel ejection device controlled byelectromagnetic valves. First NMDA was repeatedly administered untilstabilization of responses, then it was given in the presence of thetest compound. The degree of inhibition—expressed as percentage—wascalculated from the peak currents evoked by NMDA in the presence andabsence of the test compound. Selectivity ratio (NR2B/NR2A), wascalculated as the ratio of test dose on NR1/2A transfected cells andIC₅₀ value of NMDA antagonism on NR1/NR2B expressing cells.

The results are given in Table 2.

TABLE 2 Assessment of selectivity for NR2B vs. NR2A subunit containingreceptors NR1/NR2A** NR1/NR2B* % Inhibition of NMDA IC₅₀ Ca²⁺-responseCompound [μM] 15 μM Selectivity 4570001461 0.015 14.9 >1000 45700022600.030 3.3 >500 CP-101,606 0.033 −8.8 >1200

-   *: Data obtained on HEK293 cells stably expressing NR1a/NR2B    subunits by measurement of intracellular calcium concentration with    a plate reader fluorimeter. Means of 3 experiments are given.-   **: results of patch clamp experiments on NR1a/NR2A transiently    transfected HEK cells.    Test concentration was as indicated. Means of 3, 6, 2 experiments    are given for 4570001461, 4570002260 and CP-101, 606 respectively.    Selectivity: selectivity ratio (NR2B/NR2A), calculated as ratio of    test concentration on NR1/NR2A transfected cells and IC₅₀ value on    NR1/NR2B expressing cells.

According to the results in Table 2, compounds 4570001461 and 4570002260as well as CP-101, 606 are highly selective toward NR2B subunitcontaining NMDA receptors.

The synthesis of compounds and pharmaceutical compositions according tothe invention is illustrated by the following not limiting Examples. Thecode numbers of the compounds, which are referred in the biologicaltests, are given after the name of the compounds prepared in theExamples.

EXAMPLE 16-(4-Benzylpiperidin-1-carbonyl)-3H-furo[3′,2′:4,5]benzo[1,2-d]oxazole-2-one(45 14255) a) Ethyl 3H-furo[2,3-f]benzoxazole-2-one-6-carboxylate

A mixture of 0.9 g (4.2 mmol) of ethyl5-hydroxy-6-aminobenzofuran-2-carboxylate [Helv. Chim. Acta 77, 100.(1994)], 60 ml of tetrahydrofuran, 3.1 ml of 20% phosgene in toluenesolution and 2.0 ml of triethylamine is stirred at room temperature for1 h. The tetrahydrofuran is distilled off in vacuum, water is added tothe residue and the product is extracted with ethyl acetate. Thecombined organic layers are washed with 5% aqueous sodiumhydrogencarbonate solution, water, 1 N hydrochloric acid solution andagain with water, dried over sodium sulfate and concentrated to yield1.0 g (96%) of the title compound as oil.

b) 3H-Furo[2,3-f]benzoxazole-2-one-6-carboxylic Acid

A stirred mixture of 1.0 g (4 mmol) of ethyl3H-furo[2,3-f]benzoxazole-2-one-6-carboxylate, 100 ml of ethanol and 0.5g of potassium hydroxide is refluxed for 1 h. The mixture isconcentrated, the residue is dissolved in water and acidified with 20%aqueous sulfuric acid solution. The precipitated crystals are filteredoff and washed with water to yield 0.84 g (95%) of the title compound.Mp.: 190-192° C. (water).

c)6-(4-Benzylpiperidin-1-carbonyl)-3H-furo[3′,2′:4,5]benzo[1,2-d]oxazole-2-one

A mixture of 0.42 g (1.9 mmol) of3H-furo[2,3-f]benzoxazole-2-one-6-carboxylic acid, 0.3 ml (2.1 mmol) oftriethylamine, 0.35 ml (2.0 mmol) of 4-benzylpiperidine, 0.76 g (2.0mmol) of HBTU (Advanced Chem. Tech.) and 10 ml of dimethylformamide isstirred at room temperature for 6 h. The reaction mixture isconcentrated and the residue is purified by column chromatography usingKieselgel 60 as adsorbent (Merck) and toluene:aceton=2:1 as eluent, thenthe product is crystallized with diethylether to yield 0.39 g (54%) ofthe title compound. Mp.: 205-210° C. (diethyl ether).

EXAMPLE 26-(4-Benzyloxypiperidin-1-carbonyl)-3H-furo[3′,2′:4,5]benzo[1,2-d]oxazole-2-one(45 14254)

The title compound is prepared from3H-furo[2,3-f]benzoxazole-2-one-6-carboxylic acid and4-benzyloxypiperidine according to the method described in Example 1/c.Mp.: 217-219° C. (diethyl ether).

EXAMPLE 31-(4-Benzylpiperidin-1-yl)-1-(1,6-dihydro-1,6-diaza-as-indacene-2-yl)methanone(45 14305) a) Methyl (Z)-2-azido-3-(1H-indole-5-yl)acrylate

Under nitrogen, to a sodium methoxide solution (prepared from 15 ml ofmethanol and 0.66 g (29 mmol) of sodium) a mixture of 1.02 g (7 mmol) ofindole-5-carbaldehyde [Helv. Chim. Acta, 1616. (1968)], 3.34 g (29 mmol)of methyl azido-acetate and 7 ml of methanol is added dropwise at 0° C.and the so obtained mixture is stirred at this temperature for 5 h. Thenthe reaction mixture is diluted with 50 ml of water, and extracted threetimes with 50 ml of chloroform. The combined organic layers are washedwith 20 ml of water, filtered through a phase separating filter-paperand concentrated to yield 1.3 g (77%) of the title compound. Mp.:130-133° C. (chloroform).

b) Methyl 1,6-dihydro-1,6-diaza-as-indacene-2-carboxylate

To a boiling solution of 36 ml of xylene 1.09 g (4.5 mmol) of methyl(Z)-2-azido-3-(1H-indole-5-yl)acrylate is added in small portions. Thereaction mixture is refluxed till the end of the nitrogen gas formation,then concentrated and the residue is crystallized with hexane, theproduct is filtered and washed with hexane to yield 0.6 g (62%) of thetitle compound. Mp.: 183-184° C. (hexane).

c) 1,6-Dihydro-1,6-diaza-as-indacene-2-carboxylic Acid

A mixture of 0.53 g (2.5 mmol) of methyl1,6-dihydro-1,6-diaza-as-indacene-2-carboxylate, 0.36 g (2.5 mmol) ofpotassium trimethylsilanolate (Aldrich) and 6.0 ml of tetrahydrofuran isrefluxed for 1 h, further 0.18 g (1.251 mmol) of potassiumtrimethylsilanolate is added and after 5 h reflux the reaction mixtureis concentrated. The residue is mixed with 20 ml of water, theundissolved material is filtered off, 0.32 ml of hydrochloric acid isadded to the filtrate, the precipitated crude product is filtered offand purified by column chromatography using Kieselgel 60 (Merck) asadsorbent, and chloroform:methanol=9:1 as eluent. The product iscrystallized with diethyl ether to yield 0.22 g (44%) of the titlecompound. Mp.: 248-250° C. (diethyl ether).

d)1-(4-Benzylpiperidin-1-yl)-1-(1,6-dihydro-1,6-diaza-as-indacene-2-yl)methanone

The title compound is prepared from1,6-dihydro-1,6-diaza-as-indacene-2-carboxylic acid and4-benzylpiperidine according to the method described in Example 1/c.Mp.: 186-188° C. (diethyl ether).

EXAMPLE 4(4-Benzylpiperidin-1-yl)-(2-propyl-8H-oxazolo[5,4-g]indol-7-yl)methanone(4570001079) a)1-(4-Benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indole-2-yl)methanone

A mixture of 5.0 g (28.2 mmol) of 6-hydroxy-indole-2-carboxylic acid [J.Chem. Soc. 1605-1608. (1948)], 4.4 ml (31.6 mmol) of triethylamine, 5.0g (28.5 mmol) of 4-benzylpiperidine, 12.0 g (31.6 mmol) of HBTU(Advanced Chem. Tech.) and 50 ml of dimethylformamide is stirred at roomtemperature for 6 h. The precipitated product is filtered off andrecrystallized from ethanol to yield 6.75 g (71%) of the title compound.Mp: 214-215° C. (ethanol).

b)(4-Benzylpiperidin-1-yl)-(2-propyl-8H-oxazolo[5,4-g]indol-7-yl)methanone

Under argon, to a solution of 0.5 g (1.49 mmol) of1-(4-benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indole-2-yl)methanone and0.14 g (0.2 mmol) of n-butylamine in 100 ml of ethylene glycol dimethylether 10 g (115 mmol) of manganese dioxide is added portion-wise at 0°C. After stirring for 1 h, the reaction mixture is filtered, thefiltrate is concentrated and the residue is purified by columnchromatography using Kieselgel 60 as adsorbent (Merck) and hexane:ethylacetate=2:1 as eluent to yield 0.1 g (17.3%) of the title compound. Mp.:195-196° C. (hexane-ethyl acetate).

EXAMPLE 56-(4-Benzylpiperidin-1-carbonyl)-1,5-dihydro-oxazolo[4,5-f]indole-2-one(4570001461) a) Methyl (Z)-2-azido-3-(4-benzyloxy-3-nitrophenyl)acrylate

Under argon, to a sodium methoxide solution (prepared from 2.5 g (108.7mmol) of sodium and 70 ml of methanol) a mixture of 6.1 g (23.7 mmol) of4-benzyloxy-3-nitrobenzaldehyde and 11.2 g (97.3 mmol) of methylazidoacetate in 100 ml of methanol is added at 0° C. The mixture isstirred at 0° C. for 5 h, then diluted with 350 ml of water, theprecipitated crystalls were filtered off, washed with water and dried toyield 4.93 g (59%) of the title compound. Mp.: 95-96° C. (water).

b) Methyl 6-benzyloxy-5-nitro-indole-2-carboxylate

To a stirred solution of 200 ml of boiling xylene 4.93 g ((13.9 mmol) ofmethyl (Z)-2-azido-3-(4-benzyloxy-3-nitrophenyl)acrylate is added insmall portions. After completion of the addition the reaction mixture isrefluxed until the gas formation is over (about 0.5 h), then cooled toroom temperature, the precipitated product is filtered off and washedwith n-hexane to yield 0.67 g (15%) of the title compound. Mp.: 184-187°C. (xylene).

c) Methyl 5-amino-6-hydroxy-indole-2-carboxylate

A mixture of 0.67 g (2.0 mmol) of methyl6-benzyloxy-5-nitro-indole-2-carboxylate, 60 ml of tetrahydrofuran and0.1 g of 10% Pd/C catalyst is hydogenated for 5 h. The catalyst isfiltered off and the filtrate containing the title compound is usedimmediately in the next step.

d) Methyl 2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylate

The title compound is prepared from methyl5-amino-6-hydroxy-indole-2-carboxylate according to the method describedin Example 1/a. Mp.: 267-277° C. (water).

e) 2-Oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylic Acid

The title compound is prepared from methyl2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylate according to themethod described in Example 1/b. Mp.: 288-290° C. (water).

f)6-(4-Benzylpiperidin-1-carbonyl)-1,5-dihydro-oxazolo[4,5-f]indole-2-one

The title compound is prepared from2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylic acid and4-benzylpiperidine according to the method described in Example 1/c.Mp.: 270-271° C. (diethyl ether).

EXAMPLE 66-(4-Benzyloxypiperidin-1-carbonyl)-1,5-dihydro-oxazolo[4,5-f]indole-2-one(4570001462)

The title compound is prepared from2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylic acid and4-benzyloxypiperidine [Tetrahedron 54, 13981, (1998)] according to themethod described in Example 1/c. Mp.: 258-261° C. (diethyl ether).

EXAMPLE 76-[4-(4-Fluorobenzyl)piperidin-1-carbonyl]-1,5-dihydro-oxazolo[4,5-f]indole-2-one(4570001484)

The title compound is prepared from2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylic acid and4-(4-fluorobenzyl)piperidine [J. Med. Chem., 35, 4903, (1992)] accordingto the method described in Example 1/c. Mp.: 244-247° C. (diethylether).

EXAMPLE 8[4-(4-Fluorobenzyl)piperidin-1-yl]-(1,6-dihydro-pirrolo[2,3-g]indazol-7-yl)-methanone(the Other Tautomeric Form of the Compound is[4-(4-fluorobenzyl)piperidin-1-yl]-(3,6-dihydro-pirrolo[2,3-g]indazol-7-yl)-methanone)(4570001661) a) Ethyl 2-[(1H-indazol-6-yl)-hydrazono]-propionate (theOther Tautomeric Form of the Compound is Ethyl2-[(3H-indazol-6-yl)-hydrazono]-propionate)

To a stirred mixture of 6.66 g (50 mmol) of 6-aminoindazole, 40 ml ofwater and 25 ml of concentrated hydrochloric acid a solution of 3.5 gsodium nitrite in 10 ml of water is added dropwise at 0° C., andstirring is continued at this temperature for 0.5 h. Then the soobtained solution is added to the following stirred mixture: 86 ml ofwater, 15 g of potassium hydroxide, 15 g of sodium acetate, 60 ml ofethanol and 8 ml of ethyl 2-methyl-acetoacetate (purity 90%). After theaddition the reaction mixture is stirred at 0° C. for 1 h, theprecipitated product is filtered off, washed with water and dried toyield 8.16 g (66%) of the title compound. Mp.: 210-211° C. (ethanol).

b) Ethyl 1,6-dihydro-pyrrolo[2,3-g]indazole-7-carboxylate (the OtherTautomeric Form of the Compound is Ethyl3,6-dihydro-pyrrolo[2,3-g]indazole-7-carboxylate)

A mixture of 4.0 g (16.2 mmol) of ethyl2-[(1H-indazol-6-yl)-hydrazono]-propionate and 20 g of polyphosphoricacid is slowly warmed to 120° C. and kept at this temperature for 0.5 h.Then the reaction mixture is cooled to room temperature, 30 ml of waterand 15 ml of concentrated hydrochloric acid is added. The so obtainedmixture is extracted with ethyl acetate, dried over sodium sulfate andconcentrated to yield 1.6 g (43%) of the title compound. Mp.: 120-121°C. (ethyl acetate).

c) 1,6-Dihydro-pyrrolo[2,3-g]indazole-7-carboxylic acid (the OtherTautomeric Form of the Compound is3,6-dihydro-pyrrolo[2,3-g]indazole-7-carboxylic Acid)

The title compound is prepared from ethyl1,6-dihydro-pyrrolo[2,3-g]indazole-7-carboxylate according to the methoddescribed in Example 1/b. Mp.: 270-275° C. (water).

d)[4-(4-Fluorobenzyl)piperidin-1-yl)-(1,6-dihydro-pirrolo[2,3-g]indazol-7-yl)-methanone(the Other Tautomeric Form of the Compound is[4-(4-fluorobenzyl)piperidin-1-yl)-(3,6-dihydro-pirrolo[2,3-g]indazol-7-yl)-methanone)

The title compound is prepared from1,6-dihydro-pyrrolo[2,3-g]indazole-7-carboxylic acid and4-(4-fluorobenzyl)piperidine according to the method described inExample 1/c. Mp.: 162-165° C. (diethyl ether).

EXAMPLE 9(4-Benzylpiperidin-1-yl)-(1,6-dihydro-pirrolo[2,3-g]indazol-7-yl)-methanone(the Other Tautomeric Form of the Compound is(4-benzylpiperidin-1-yl)-(3,6-dihydro-pirrolo[2,3-g]indazol-7-yl)-methanone)(4570001662)

The title compound is prepared from1,6-dihydro-pyrrolo[2,3-g]indazole-7-carboxylic acid and4-benzylpiperidine according to the method described in Example 1/c.Mp.: 209-210° C. (diethyl ether).

EXAMPLE 10[4-(4-Fluorobenzyl)piperidin-1-yl]-(3,6-dihydro-imidazo[4,5-e]indol-7-yl)methanone(the Other Tautomeric Form of the Compound is[4-(4-fluorobenzyl)piperidin-1-yl]-(1,6-dihydro-imidazo[4,5-e]indol-7-yl)methanone)(4570001688) a) Ethyl 2-[(1H-benzimidazol-5-yl)-hydrazono]-propionate(the Other Tautomeric Form of the Compound is Ethyl2-[(3H-benzimidazol-5-yl)-hydrazono]-propionate)

The title compound is prepared from 5-amino-benzimidazole [Helv. Chim.Acta, 32, 135 (1949)] according to the method described in Example 8/a.Mp.: 121-127° C. (water).

b) Ethyl 3,6-dihydro-imidazo[4,5-e]indole-7-carboxylate (the OtherTautomeric Form of the Compound is Ethyl1,6-dihydro-imidazo[4,5-e]indole-7-carboxylate)

The title compound is prepared from ethyl2-[(1H-benzimidazol-5-yl)-hydrazono]-propionate according to the methoddescribed in Example 8/b. Mp.: foam.

c) 3,6-Dihydro-imidazo[4,5-e]indole-7-carboxylic Acid (the OtherTautomeric Form of the Compound is1,6-dihydro-imidazo[4,5-e]indole-7-carboxylic Acid)

The title compound is prepared from ethyl3,6-dihydro-imidazo[4,5-e]indole-7-carboxylate according to the methoddescribed in Example 1/b. Mp.: 185-190° C. (water).

d)[4-(4-Fluorobenzyl)piperidin-1-yl]-(3,6-dihydro-imidazo[4,5-e]indol-7-yl)methanone(the Other Tautomeric Form of the Compound is[4-(4-fluorobenzyl)piperidin-1-yl]-(1,6-dihydro-imidazo[4,5-e]indol-7-yl)methanone

The title compound is prepared from3,6-dihydro-imidazo[4,5-e]indole-7-carboxylic acid and4-(4-fluorobenzyl)piperidine according to the method described inExample 1/c. Mp.: 283-287° C. (diethyl ether).

EXAMPLE 11(4-Benzylpiperidin-1-yl)-(3,6-dihydro-pirrolo[3,2-e]indazol-7-yl)methanone(the Other Tautomeric Form of the Compound is(4-benzylpiperidin-1-yl)-(1,6-dihydro-pirrolo[3,2-e]indazol-7-yl)methanone)(4570001689) a) Ethyl 2-[(1H-indazol-5-yl)-hydrazono]-propionate (theOther Tautomeric Form of the Compound is Ethyl2-[(3H-indazol-5-yl)-hydrazono]-propionate)

The title compound is prepared from 5-aminoindazole according to themethod described in Example 8/a. Mp.: 111-113° C. (water).

b) Ethyl 3,6-dihydro-pyrrolo[3,2-e]indazole-7-carboxylate (the OtherTautomeric Form of the Compound is Ethyl1,6-dihydro-pyrrolo[3,2-e]indazole-7-carboxylate)

The title compound is prepared from ethyl2-[(1H-indazol-5-yl)-hydrazono]-propionate according to the methoddescribed in Example 8/b. Mp.: 220-221° C. (methanol).

c) 3,6-Dihydro-pyrrolo[3,2-e]indazole-7-carboxylic Acid (the OtherTautomeric Form of the Compound is1,6-dihydro-pyrrolo[3,2-e]indazole-7-carboxylic Acid)

The title compound is prepared from ethyl3,6-dihydro-pyrrolo[3,2-e]indazole-7-carboxylate according to the methoddescribed in Example 1/b. Mp.: 183-189° C. (water).

d)(4-Benzylpiperidin-1-yl)-(3,6-dihydro-pirrolo[3,2-e]indazol-7-yl)methanone(the Other Tautomeric Form of the Compound is(4-benzylpiperidin-1-yl)-(1,6-dihydro-pirrolo[3,2-e]indazol-7-yl)methanone)

The title compound is prepared from3,6-dihydro-pyrrolo[3,2-e]indazole-7-carboxylic acid and4-benzylpiperidine according to the method described in Example 1/c.Mp.: 205-207° C. (diethyl ether).

EXAMPLE 12[4-(4-Fluorobenzyl)piperidin-1-yl]-(3,6-dihydro-pirrolo[3,2-e]indazol-7-yl)methanone(the Other Tautomeric Form of the Compound is[4-(4-fluorobenzyl)piperidin-1-yl]-(1,6-dihydro-pirrolo[3,2-e]indazol-7-yl)methanone)(4570001690)

The title compound is prepared from3,6-dihydro-pyrrolo[3,2-e]indazole-7-carboxylic acid and4-(4-fluorobenzyl)piperidine according to the method described inExample 1/c. Mp.: 169-173° C. (diethyl ether).

EXAMPLE 13(4-Benzylpiperidin-1-yl)-(3,6-dihydro-imidazo[4,5-e]indol-7-yl)methanone(the Other Tautomeric Form of the Compound is(4-benzylpiperidin-1-yl)-(1,6-dihydro-imidazo[4,5-e]indol-7-yl)methanone)(4570001779)

The title compound is prepared from3,6-dihydro-imidazo[4,5-e]indole-7-carboxylic acid and4-benzylpiperidine according to the method described in Example 1/c.Mp.: 256-257° C. (diethyl ether).

EXAMPLE 147-(4-Benzylpiperidin-1-carbonyl)-1,6-dihydro-3-oxa-1,6,8-triaza-as-indacen-2-one(the Other Tautomeric Form of the Compound is7-(4-benzylpiperidin-1-carbonyl)-1,8-dihydro-3-oxa-1,6,8-triaza-as-indacen-2-one)(4570001971) a) N-Butyl-N′-(4-methoxy-2-nitrophenyl)-oxalamide

To a suspension of 44.0 g (164 mmol) ofN-(4-methoxy-2-nitrophenyl)-oxalamic acid ethyl ester [J. Med. Chem.,18, 926 (1975)] in 330 ml of toluene 16.8 ml (170 mmol) of n-butylamineis added dropwise keeping the temperature below 20° C., then the mixtureis stirred at room temperature overnight. The reaction mixture isconcentrated and 200 ml of diethyl ether is added to the residue. The soobtained suspension is filtered, washed with diethyl ether and dried toyield 45.3 g (93%) of the title compound. Mp.: 127-128° C. (diethylether).

b) N-(2-Amino-4-methoxyphenyl)-N′-butyl-oxalamide

A mixture of 27.0 g (91 mmol) ofN-butyl-N′-(4-methoxy-2-nitrophenyl)-oxalamide, 1200 ml of methanol and7.3 g of 10% Pd/C catalyst is hydogenated for 3 h. The catalyst isfiltered off, washed with aceton, the filtrate is concentrated and theresidue is treated with 100 ml of diethyl ether. The obtained product isfiltered, washed with diethyl ether a nd dried to yield 21.8 g (90%) ofthe title compound. Mp.: 180-181° C. (diethyl ether).

c) 6-Methoxy-1H-benzimidazole-2-carboxylic Acid Butylamide (the OtherTautomeric Form of the Compound is5-methoxy-1H-benzimidazole-2-carboxylic Acid Butylamide)

Under nitrogen, 41.0 g (154 mmol) ofN-(2-amino-4-methoxyphenyl)-N′-butyl-oxalamide is heated to 240° C. for10 min. After cooling the residue is treated with 300 ml of aceton,filtered and the filtrate is concentrated. The so obtained residue iscrystallized with 150 ml of hexane, filtered and dried to yield 26.5 g(69.5%) of the title compound. Mp.: 125-126° C. (hexane).

d) 6-Hydroxy-1H-benzimidazole-2-carboxylic Acid (the Other TautomericForm of the Compound is 5-hydroxy-1H-benzimidazole-2-carboxylic Acid)

A solution of 26.0 g (105 mmol) of6-methoxy-1H-benzimidazole-2-carboxylic acid butylamide in 780 ml of 48%hydrogen bromide is stirred at 90° C. for 12 h, then at 125° C. for 12h. The reaction mixture is cooled, the precipitated product is filteredoff, washed with water and dried to yield 14.4 g (76%) of the titlecompound. Mp.: 206-207° C. (water).

e) 6-Hydroxy-7-nitro-1H-benzimidazole-2-carboxylic Acid (the OtherTautomeric Form of the Compound is5-hydroxy-4-nitro-1H-benzimidazole-2-carboxylic Acid)

To a solution of 2.0 g (11.2 mmol) of6-hydroxy-1H-benzimidazole-2-carboxylic acid in 25 ml of trifluoroaceticacid 1.0 g (11.7 mmol) of sodium nitrate is added below 20° C. and themixture is stirred at 20° C. for 2 h. The reaction mixture is pouredinto ice-water, the precipitated product is filtered off, washed withwater and dried to yield 1.7 g (68%) of the title compound. Mp.: 218° C.(water).

f)(4-Benzylpiperidin-1-yl)-(6-hydroxy-7-nitro-1H-benzimidazol-2-yl)methanone(the Other Tautomeric Form of the Compound is(4-benzylpiperidin-1-yl)-(5-hydroxy-4-nitro-1H-benzimidazol-2-yl)methanone)

The title compound is prepared from6-hydroxy-7-nitro-1H-benzimidazole-2-carboxylic acid and4-benzylpiperidine according to the method described in Example 1/c.Mp.: 102° C. (diethyl ether).

g)(7-Amino-6-hydroxy-1H-benzimidazol-2-yl)-(4-benzylpiperidin-1-yl)methanone(the Other Tautomeric Form of the Compound is(4-amino-5-hydroxy-1H-benzimidazol-2-yl)-(4-benzylpiperidin-1-yl)methanone

A mixture of 1.0 g of(4-benzylpiperidin-1-yl)-(6-hydroxy-7-nitro-1H-benzimidazol-2-yl)methanone,30 ml of methanol and 0.4 g of 10% Pd/C catalyst is hydogenated for 2 h.The catalyst is filtered off and the filtrate is concentrated. Theresidue is treated with diethyl ether, the crystalline product isfiltered, washed with diethyl ether and dried to yield 0.5 g (54%) ofthe title compound. Mp.: 108° C. (diethyl ether).

h)7-(4-Benzylpiperidin-1-carbonyl)-1,6-dihydro-3-oxa-1,6,8-triaza-as-indacen-2-one(the Other Tautomeric Form of the Compound is7-(4-benzylpiperidin-1-carbonyl)-1,8-dihydro-3-oxa-1,6,8-triaza-as-indacen-2-one)

To a solution of 0.45 g (1.28 mmol) of(7-amino-6-hydroxy-1H-benzimidazol-2-yl)-(4-benzylpiperidin-1-yl)methanonein 5 ml of tetrahydrofuran 0.2 g (1.37 mmol) of 1,1′-carbonyldiimidazoleis added at 20° C. The reaction mixture is stirred at room temperaturefor 2 h, then concentrated. The residue is purified by columnchromatography using Kieselgel 60 as adsorbent (Merck) andtoluene:methanol=4:1 as eluent. The so obtained product is crystallizedwith isopropanol, filtered and dried to yield 0.45 g (93.5%) of thetitle compound. Mp.: >270° C. (isopropanol).

EXAMPLE 156-(4-Benzylpiperidin-1-carbonyl)-3,5-dihydro-imidazo[4′,5′;4,5]benzo[1,2-d]oxazole-2-one(the Other Tautomeric Form of the Compound is6-(4-benzylpiperidin-1-carbonyl)-3,7-dihydro-imidazo[4′,5′;4,5]benzo[1,2-d]oxazole-2-one)(4570001972) a) 6-Amino-5-nitro-3H-benzoxazol-2-one

To a solution of 2.0 g (13.3 mmol) of 6-amino-3H-benzoxazol-2-one [J.Chem. Soc., 321 (1938)] in 20 ml of trifluoroacetic acid 1.2 g (14.1mmol) of sodium nitrate is added below 20° C. The reaction mixture isstirred at room temperature overnight, then concentrated. The residue ispurified by column chromatography using Kieselgel 60 as adsorbent(Merck) and toluene:methanol=4:1 as eluent to yield. 2.50 g (96%) of thetitle compound. Mp.: 198° C. (toluene-methanol).

b) (4-Benzylpiperidin-1-yl)oxoacetic Acid Ethyl Ester

To a solution of 10 g (57 mmol) of 4-benzylpiperidine and 10 ml (57.4mmol) of N-ethyldiisopropylamine in 100 ml of dichloromethane 7.05 ml(63.1 mmol) of ethyl oxalyl chloride is added dropwise at 0° C., thenthe mixture is stirred at this temperature for 30 min. The reactionmixture is diluted with water, separated, the organic layer is dried andconcentrated to yield 15.5 g (99%) of the title compound as an oil.

c) (4-Benzylpiperidin-1-yl)oxoacetic Acid

A mixture of 15.5 g (56 mmol) of (4-benzylpiperidin-1-yl)oxoacetic acidethyl ester, 5 g (79.4 mmol) of potassium hydroxide and 250 ml ofmethanol is stirred at room temperature for 6 h. Then reaction mixtureis concentrated, the residue is taken up in water, acidified with 1Nhydrochloric acid, the precipitated product is filtered off, washed withwater and dried to yield 11.95 g (85%) of the title compound. Mp.: 115°C. (water).

d) (4-Benzylpiperidin-1-yl)oxoacetyl Chloride

A mixture of 26.2 g (106 mmol) of (4-benzylpiperidin-1-yl)oxoacetic acidand 50 ml of thinyl chloride is refluxed for 2 h, then cooled andconcentrated to yield 28.0 g (99.5%) of the title compound as an oil.

e)2-(4-Benzylpiperidin-1-yl)-N-(5-nitro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-oxo-acetamide

To a solution of 3.23 g (16.56 mmol) of6-amino-5-nitro-3H-benzoxazole-2-one (step a), 2.58 ml (18.5 mmol) oftrethylamine and 100 ml of chloroform 5.25 g (19.75 mmol) of(4-benzylpiperidin-1-yl)oxoacetyl chloride in 20 ml of chloroform isadded dropwise at 20° C., then the mixture is stirred at roomtemperature for 2 h. The mixture is washed with water, the organic layeris dried and concentrated. The residue is purified by columnchromatography using Kieselgel 60 as adsorbent (Merck) andtoluene:methanol=4:1 as eluent to yield 3.3 g (47%) of the titlecompound. Mp.: foam.

f)N-(5-Amino-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-(4-benzylpiperidin-1-yl)-2-oxo-acetamide

A mixture of 3.3 g (7.7 mmol) of2-(4-benzylpiperidin-1-yl)-N-(5-nitro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-oxo-acetamide,100 ml of methanol and 0.3 g of 10% Pd/C catalyst is hydrogenated for 8h. The catalyst is filtered off and the filtrate is concentrated. Theresidue is purified by column chromatography using Kieselgel 60 asadsorbent (Merck) and toluene:acetone=2:1 as eluent to yield 1.06 g(34.5%) of the title compound. Mp.: 296° C. (toluene-acetone).

g)6-(4-Benzylpiperidin-1-carbonyl)-3,5-dihydro-imidazo[4′,5′;4,5]benzo[1,2-d]oxazole-2-one(the Other Tautomeric Form of the Compound is6-(4-benzylpiperidin-1-carbonyl)-3,7-dihydro-imidazo[4′,5′;4,5]benzo[1,2-d]oxazole-2-one)

1.0 g (2.5 mmol) ofN-(5-amino-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-(4-benzylpiperidin-1-yl)-2-oxo-acetamideis heated to 240° C. for 10 min, then cooled. The obtained mixture ispurified by column chromatography using Kieselgel 60 as adsorbent(Merck) and toluene:acetone=1:1 as eluent to yield 0.16 g (17%) of thetitle compound. Mp.: >290° C. (toluene-acetone).

EXAMPLE 166-(4-Benzylpiperidin-1-carbonyl)-3,5-dihydro-1H-imidazo[4,5-f]indole-2-one(4570002045) a) Ethyl2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-hydrazono]-propionate

The title compound is prepared from5-amino-1,3-dihydro-benzimidazol-2-one [J. Am. Chem. Soc., 80, 1657(1958)] according to the method described in Example 8/a. Mp.: 220° C.(water).

b) Ethyl 2-oxo-1,2,3,5-tetrahydro-imidazo[4,5-f]indole-6carboxylate

The title compound is prepared from ethyl2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-hydrazono]-propionateaccording to the method described in Example 8/b. Mp.: 196-197° C.(ethyl acetate).

c) 2-Oxo-1,2,3,5-tetrahydro-imidazo[4,5-f]indole-6-carboxylic Acid

The title compound is prepared from ethyl2-oxo-1,2,3,5-tetrahydro-imidazo[4,5-f]indole-6-carboxylate_according tothe method described in Example 1/b. Mp.: >270° C. (water).

d)6-(4-Benzylpiperidin-1-carbonyl)-3,5-dihydro-1H-imidazo[4,5-f]indole-2-one

The title compound is prepared from2-oxo-1,2,3,5-tetrahydro-imidazo[4,5-f)indole-6-carboxylic acid and4-benzylpiperidine according to the method described in Example 1/c.Mp.: >270° C. (acetonitrile).

EXAMPLE 172-(4-Benzylpiperidin-1-carbonyl)-1,5-dihydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-6-one(4570002185) a) Methyl6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-2-carboxylate

To a solution of 2.0 g (9.7 mmol) of methyl5-amino-6-hydroxy-indole-2-carboxylate (Example 5/c) in 300 ml oftetrahydrofuran 2.45 g (29.2 mmol) of sodium hydrogencarbonate and 1.3ml (16.3 mmol) of chloroacetyl chloride are added and the mixture isstirred at room temperature overnight. The reaction mixture isconcentrated and 100 ml of water is added to the residue. Theprecipitated crystalls are filtered off, washed with water and suspendedin 120 ml of acetonitrile. 4.05 g (29.3 mmol) of potassium carbonate isadded to the suspension and the resulted mixture is stirred at roomtemperature overnight. The reaction mixture is concentrated and 100 mlof water is added to the residue. The product is filtered off, washedwith water and dried to yield 1.7 g (71%) of the title compound. Mp.:188-196° C. (water).

b)6-Oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-2-carboxylicAcid

The title compound is prepared from methyl6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-2-carboxylate according to the method described inExample 8/b. Mp.: 231-237° C. (water).

c)2-(4-Benzylpiperidin-1-carbonyl)-1,5-dihydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-6-one

The title compound is prepared from6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-2-carboxylicacid and 4-benzylpiperidine according to the method described in Example1/c. Mp.: 225-231° C. (diethyl ether).

EXAMPLE 182-[4-(4-Fluorobenzyl)piperidin-1-carbonyl]-1,5-dihydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-6-one(4570002193)

The title compound is prepared from6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-2-carboxylicacid and 4-(4-fluorobenzyl)piperidine according to the method describedin Example 1/c. Mp.: 219-226° C. (diethyl ether).

EXAMPLE 19(3,6-Dihydro-pirrolo[3,2-e]indazol-7-yl)-(4-p-tolyloxypiperidin-1-yl)methanone(the Other Tautomeric Form of the Compound is(1,6-dihydro-pirrolo[3,2-e]indazol-7-yl)-(4-p-tolyloxypiperidin-1-yl)methanone)(4570002260)

The title compound is prepared from3,6-dihydro-pyrrolo[3,2-e]indazole-7-carboxylic acid (Example 11/c) and4-p-tolyloxypiperidine [J. Med. Chem., 21, 309 (1978)] according to themethod described in Example 1/c. Mp.: 218-222° C. (diethyl ether).

EXAMPLE 20(3,6-Dihydro-pirrolo[3,2-e]indazol-7-yl)-[4-(4-methylbenzyl)piperidin-1-yl]methanone(the Other Tautomeric Form of the Compound is(1,6-dihydro-pirrolo[3,2-e]indazol-7-yl)-[4-(4-methylbenzyl)piperidin-1-yl]methanone)(4570002340)

The title compound is prepared from3,6-dihydro-pyrrolo[3,2-e]indazole-7-carboxylic acid (Example 11/c) and4-(4-methylbenzyl)piperidine [J. Org. Chem., 64, 3763 (1999)] accordingto the method described in Example 1/c. Mp.: 253-255° C. (diethylether).

EXAMPLE 211-(4-Benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indole-2-yl)methanone (4513579)

A mixture of 5.0 g (28.2 mmol) of 6-hydroxy-indole-2-carboxylic acid [J.Chem. Soc. 1605-1608. (1948)], 4.4 ml (31.6 mmol) of triethylamine, 5.0g (28.5 mmol) of 4-benzylpiperidine, 12.0 g (31.6 mmol) of HBTU(Advanced Chem. Tech.) and 50 ml of dimethylformamide is stirred at roomtemperature for 6 h. The precipitated product is filtered off andrecrystallized from ethanol to yield 6.75 g (71%) of the title compound.Mp: 214-215° C. (ethanol).

EXAMPLE 221-[4-(4-Fluorobenzyl)piperidine-1-yl]-1-(6-hydroxy-1H-indole-2-yl)methanone(45 13848)

The title compound is prepared from 4-(4-fluorobenzyl)piperidine [J.Med. Chem., 35, 4903. (1992)] and 6-hydroxy-1H-indole-2-carboxylic acidin acetonitrile at room temperature. The reaction mixture isconcentrated and the residue is purified by column chromatography usingKiesel gel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent.Mp.: 180-182° C. (toluene).

EXAMPLE 231-(4-Benzylpiperidine-1-yl)-1-(5-nitro-1H-indole-2-yl)methanone (4514205)

The title compound is prepared from 5-nitroindole-2-carboxylic acid (J.Am. Chem. Soc., 4621 (1958)] and 4-benzylpiperidine according to themethod described in Example 1/c. Mp.: 220-224° C. (diethylether).

EXAMPLE 241-(5-Amino-1H-indole-2-yl)-1-(4-benzylpiperidine-1-yl)methanone (4514244)

A mixture of 0.5 g (1.38 mmol) of1-(4-benzylpiperidine-1-yl)-1-(5-nitro-1H-indole-2-yl)methanone, 20 mlof methanol and 0.1 g of 10% Pd/C catalyst is hydrogenated for 5 h. Thecatalyst is filtered off, washed with methanol and the filtrate isconcentrated. The residue is treated with diethylether and theprecipitated crystals are filtered off to yield 0.27 g (59%) of thetitle compound. Mp.: 175-180° C. (diethylether).

EXAMPLE 25(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-benzoimidazol-2-yl)-methanone(45 70001103) a) N-Butyl-N′-(4-methoxy-2-nitro-phenyl)oxalamide

To a suspension of 44.0 g (164 mmol) ofN-(4-methoxy-2-nitro-phenyl)oxalamic acid ethyl ester [J. Med. Chem.,18, 926 (1975)] and 330 ml toluene 16.8 ml (170 mmol) of n-butylamin isadded under 20° C. The reaction mixture is stirred at room temperaturefor 10 h, then concentrated and the residue is crystallized with diethylether, the precipitated product is filtered off, washed with diethylether and dried to yield 45.3 g (93.3%) of the title compound. Mp.:127-128° C. (diethyl ether).

b) N-(2-Amino-4-methoxy-phenyl)-N′-butyl-oxalamide

A mixture of 27.0 g (91 mmol) of N-Butyl-N′-(4-methoxy-2-nitro-phenyl)oxalamide, 1200 ml of methanol and 7.3 g of 5% Pd/C catalyst ishydrogenated from 3 h. To the reaction mixture is added 600 ml ofacetone. The catalyst is filtered off, washed with acetone, the filtrateis concentrated and the residue si crystallized with diethyl ether toyield 21.8 g (90.1%) of the titled compound. Mp.: 180-181° C. (diethylether).

c) 6-Methoxy-1H-benzoimidazole-2-carboxylic Acid Butylamide

Under nitrogen, 41.0 g (154 mmol) ofN-(2-amino-4-methoxy-phenyl)-N′-butil-oxalamide is stirred at 240° C.for 10 min. The mixture is cooled to room temperature then 300 ml ofacetone is added, and stirred for 1 h. The precipitated product isfiltered off. The filtrate is concentrated and the residue is mixed with150 ml of n-hexane. The precipitated product is filtered off, washedwith hexane and dried to yield 26.5 g (69.5%) of the title compound.Mp.: 125-126° C. (n-hexane).

d) 6-Hydroxy-1H-benzoimidazole-2-carboxylic Acid

A mixture of 26.0 g (105 mmol) of6-methoxy-1H-benzoimidazole-2-carboxylic acid butilamide and 780 ml of48% aqueus hydrobromic acid is stirred at 110° C. for 8 h, then refluxedfor 12 h. The mixture is cooled to room temperature, the precipitatedproduct is filtered off, washed with water until pH neutral and dried toyield 14.3 g (76.2%) of the title compound. Mp.: 206-207° C. (water).

e) (4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-benzoimidazol-2-yl)-methanone(45 70001103)

A mixture of 3.0 g (16.75 mmol) of6-hydroxi-1H-benzoimidazol-2-carboxilic acid, 2.4 ml (17.2 mmol) oftriethylamin, 3.0 g (17.1 mmol) of 4-benzyl-piperidine, 7.0 g (18.5mmol) of HBTU and 100 ml of dimethylformamide is stirred at roomtemperature for 16 h. The reaction mixture is concentrated and theresidue is purified by column chromatography using Kieselgel 60 asadsorbent (Merck) and toluene:methanol=4:1 as eluent, then the productis recrystallized from toluene to yield 3.58 g (63.5%) of the titlecompound. Mp.: 186° C. (toluene).

EXAMPLE 26(6-Hydroxy-1H-benzoimidazol-2-yl)-[4-(4-methyl-benzyl)-piperidine-1-yl]-methanone45 70001378

The title compound is prepared from6-hydroxy-1H-benzoimidazole-2-carboxylic acid [Example elözö d] and4-(-methylbenzyl)piperidine [J. Org. Chem., 64, 3763 (1999)] accordingto the method described in Example 25. Mp.: 93° C. (diisopropyl ether).

EXAMPLE 27

Preparation of Pharmaceutical Compositions:

a) Tablets:

0.01-50% of active ingredient, 15-50% of lactose, 15-50% of potatostarch, 5-15% of polyvinyl pyrrolidone, 1-5% of talc, 0.01-3% ofmagnesium stearate, 1-3% of colloid silicon dioxide and 2-7% ofultraamylopectin are mixed, then are granulated by wet granulation andpressed to tablets.

b) Dragées. Filmcoated Tablets:

The tablets made according to the method described above are coated by alayer consisting of entero- or gastrosolvent film, or of sugar and talc.The dragées are polished by a mixture of beeswax and carnuba wax.

c) Capsules:

0.01-50% of active ingredient, 1-5% of sodium lauryl sulfate, 15-50% ofstarch, 15-50% of lactose, 1-3% of colloid silicon dioxide and 0.01-3%of magnesium stearate are thoroughly mixed, the mixture is passedthrough a sieve and filled in hard gelatin capsules.

d) Suspensions:

Ingredients: 0.01-15% of active ingredient, 0.1-2% of sodium hydroxide,0.1-3% of citric acid, 0.05-0.2% of nipagin (sodium methyl4-hydroxybenzoate), 0.005-0.02% of nipasol, 0.01-0.5% of carbopol(polyacrilic acid), 0.1-5% of 96% ethanol, 0.1-1% of flavoring agent,20-70% of sorbitol (70% aqueous solution) and 30-50% of distilled water.

To solution of nipagin and citric acid in 20 ml of distilled water,carbopol is added in small portions under vigorous stirring, and thesolution is left to stand for 10-12 h. Then the sodium hydroxide in 1 mlof distilled water, the aqueous solution of sorbitol and finally theethanolic raspberry flavor are added with stirring. To this carrier theactive ingredient is added in small portions and suspended with animmersing homogenizator. Finally the suspension is filled up to thedesired final volume with distilled water and the suspension syrup ispassed through a colloid milling equipment.

e) Suppositories:

For each suppository 0.01-15% of active ingredient and 1-20% of lactoseare thoroughly mixed, then 50-95% of adeps pro suppository (for exampleWitepsol 4) is melted, cooled to 35° C. and the mixture of activeingredient and lactose is mixed in it with homogenizator. The obtainedmixture is mould in cooled forms.

f) Lyophilized Powder Ampoule Compositions:

A 5% solution of mannitol or lactose is made with bidistilled water forinjection use, and the solution is filtered so as to have sterilesolution. A 0.01-5% solution of the active ingredient is also made withbidistilled water for injection use, and this solution is filtered so asto have sterile solution. These two solutions are mixed under asepticconditions, filled in 1 ml portions into ampoules, the content of theampoules is lyophilized, and the ampoules are sealed under nitrogen. Thecontents of the ampoules are dissolved in sterile water or 0.9%(physiological) sterile aqueous sodium chloride solution beforeadministration.

1. A compound of the formula (I)

wherein one of the neighboring R¹, R², R³ and R⁴ groups is hydroxy, andthe others are each hydrogen atoms, R⁵ and R⁶ together with the nitrogenbetween them form a saturated or unsaturated, 4-6 membered heterocyclicring, which is substituted by phenoxy, phenyl-(C₁-C₄ alkyl),phenyl-(C₁-C₄ alkoxy), phenoxy-(C₁-C₄ alkyl), or benzoyl, optionallysubstituted on the aromatic ring by one or more halogen atoms, cyano orhydroxy groups, C₁-C₄ alkyl or C₁-C₄ alkoxy groups, X is NH—, Y is anitrogen atom, or a pharmaceutically acceptable salt thereof formed withacids or bases.
 2. A compound of the Formula (I) defined in claim 1 andselected from the group consisting of:(6-hydroxy-1H-benzimidazol-2-yl)-[4-(4-methyl-benzyl)-piperidine-1-yl]methanone;and (4-benzylpiperidin-1-yl)-6-hydroxy-1H-benzimidazol-2-yl)-methanone;or a pharmaceutically acceptable salt thereof formed with acids orbases.
 3. The compound of the Formula (I) defined in claim 1 which is(4-benzylpiperidin-1-yl)-6-hydroxy-1H-benzimidazol-2-yl)-methanone or apharmaceutically acceptable salt thereof formed with acids or bases. 4.A pharmaceutical compositions having an NR2B selective receptorantagonist effect, comprising a therapeutically effective amount of acompound of the Formula (I) as defined in claim 1 or a pharmaceuticallyacceptable salt thereof formed with acids or bases and apharmaceutically acceptable inert carrier.
 5. A method of treating painin a mammalian subject in need of the treatment which comprises the stepof administering to the mammalian subject a therapeutically effectiveamount of the compound of the Formula (I) defined in claim
 1. 6. Aprocess for preparing a compound of the Formula (I)

wherein one of the neighboring R¹, R², R³ and R⁴ groups is hydroxy, andthe others are each hydrogen atoms, R⁵ and R⁶ together with the nitrogenbetween them form a saturated or a unsaturated, 4-6 memberedheterocyclic ring, which is substituted by phenoxy, phenyl-(C₁-C₄alkyl), phenyl-(C₁-C₄ alkoxy), phenoxy-(C₁-C₄ alkyl), or benzoyl,optionally substituted on the aromatic ring by one or more halogenatoms, cyano or hydroxy groups, C₁-C₄ alkyl or C₁-C₄ alkoxy groups, X isNH—, Y is a nitrogen atom, or a pharmaceutically acceptable salt thereofformed with acids or bases, which comprises the step of: amidating acompound of the Formula (II)

wherein the meaning of R¹, R², R³, R⁴, X and Y are as defined above witha compound of the Formula (III)

wherein the meaning of R⁵ and R⁶ are as defined above, to obtain thecompound of the Formula (I) or a pharmaceutically acceptable saltthereof formed with an acid or a base, then the so obtained compound offormula (I) or pharmaceutically acceptable salt formed with an acid or abase is optionally transformed into another compound of the Formula (I)or pharmaceutically acceptable salt thereof formed with an acid or abase by introducing a new substituent and/or by modifying or removing anexisting substituent, and/or by forming a pharmaceutically acceptablesalt with an acid or base and/or by liberating a compound of the Formula(I) from its pharmaceutically acceptable salt formed with an acid orbase.
 7. The process defined in claim 6, wherein the compound of theFormula (II) undergoing amidation with the compound of the Formula(III), is in the form of an active derivative of a carboxylic acid. 8.The process defined in claim 7, wherein the compound of the Formula (II)in the form of an active derivative of a carboxylic acid is an esterformed with 0-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.
 9. The process defined in claim 7, wherein thecompound of the Formula (II) in the form of an active derivative of acarboxylic acid is an acid halogenide.
 10. The process defined in claim9, wherein the acid halogenide is an acid chloride.